Why bother? Because they ultimately want to intelligently design new life-forms from scratch—say, bacteria that can manufacture medical drugs, or algae that churn out biofuels. And creation requires understanding. “We had to start with a system where we knew and understood all the components, so that when we added specific ones to it, we could do so in a logical design way,” Venter says. They needed a minimal genome—a vanilla model that they could later kit out with deluxe accessories.
And they’ve done it. Six years after Synthia, they’ve finally unveiled their bare-bones bacterium. And in piecing together its components, they realized that they’re nowhere close to understanding them all. Of the 473 genes in their pared-down cell, 149 are completely unknown. They seem to be essential (and more on what that means later). Many of them have counterparts that are at work in your body right now, probably keeping you alive.
And they’re a total mystery.
“We’ve discovered that we don’t know a third of the basic knowledge of life,” says Venter. “We expected that maybe 5 percent of the genes would be of unknown function. We weren’t ready for 30 percent. I would have lost a very big bet.”
Back in 1996, when the team began their 20-year quest, Arcady Mushegian and Eugene Koonin estimated that the minimal genome consists of around 256 genes. (For comparison, we have 20,000 to 25,000, the well-studied E. coli has 4,000 to 5,000, and the smallest free-living bacterium Mycoplasma genitalium has 525.) Mushegian and Koonin compared M. genitalium’s minuscule genome with that of another small bacterium and found 256 overlapping genes. Those, they reasoned, “are close to the minimal set that is necessary and sufficient to sustain the existence of a modern-type cell.” Other scientists have since repeated the same exercise and arrived at a similar answer: life depends on a common core of 200 to 300 genes.
“We set out relatively certain that we could design a cell from scratch,” says Venter. “We were so cocky that we even had a contest between ourselves to see who could do it first.”
They started with Synthia’s genome and deleted 440 seemingly disposable genes, leaving just 432. Once again, they synthesized this set and transplanted it into an empty cell. Which promptly died. “Nothing worked,” says Venter. “We couldn’t get a living cell. It became clear that all those earlier studies were missing something fundamental.”
There were two big problems. The first is clear in hindsight: there are many essential genes that no one knew anything about. The second became obvious earlier: many genes are redundant. The team had been judging the worth of genes by hobbling them one by one and seeing if cells still survived. But many pairs of genes understudy for each other: losing one is no big deal but losing both is catastrophic. Put it this way: knock out either engine on a jumbo jet, and it’ll probably still fly; bill them both as “non-essential” and your plane will crash.